Cocaine is a highly addictive psychostimulant that exhibits region-specific activity throughout the brain. It is widely accepted that adolescents present a higher vulnerability to cocaine addiction than adults. Recent evidence has suggested that this increased vulnerability is biological in origin, thus raising the question of whether this age effect is due to differences in neural circuitry or local cocaine concentration in the brain. In order to investigate this and other important neuroscience questions, it is unequivocally necessary to develop cocaine sensing technology capable of directly measuring real-time transient events at multiple discrete regions throughout the brain. Current conventions for in vivo cocaine quantification (microdialysis, homogenized tissue composition, etc.) lack the necessary spatial and temporal resolution. We have recently developed an electrochemical aptamer-based in vivo cocaine sensor on a silicon based microelectrode array (MEA) platform capable of directly measuring cocaine from discrete brain locations. The sensor exhibits a detection limit of 1 M with excellent spatial and temporal resolution and can maintain a reproducible detection over the course of 3 hours. After 3 hours, performance degradation was observed likely due to biofouling and aptamer detachment. We propose to develop and apply advanced dual polymer coating strategy to improve the sensitivity and stability of the sensor. The coatings include non-conductive and conductive zwitterionic polymers that are highly resistant to biofouling. To improve the aptamer binding efficiency and stability, a novel electrically conducting polymer will be developed capable of bio-conjugation with thiolated aptamers. We hypothesize that the incorporation of these polymer coatings will improve cocaine sensor performance over long-term implantation. The specific objectives of this project are to develop the methodology to pattern these polymer coatings on MEAs for the best sensing capability and fouling resistance and then test the ability of the polymer- modifed cocaine sensor to directly measure in vivo cocaine concentration reproducibly over a period of 72 hours. The local brain concentration of cocaine upon repeated IV injection will be compared between adult and adolescent rats to determine the origin of the age effect. The proposed sensor will serve as the first ever technology capable of measuring in vivo cocaine concentration over multiple hours and days. This technology has the potential to revolutionize our understanding of cocaine abuse and addiction. Additionally, the modified microelectrodes are also able to recording neurophysiological signals. Implantable sensors with dual functionality will have a broad impact on neuroscience research. Finally, the aptamer based electrochemical sensing platform can be generalized to a broad range of important analytes, while the highly functionalizable and fouling resistant coatings can be applied to other implantable biosensors throughout a broad range of biological research fields and medical diagnosis.